CN103071153B - Ready-to-use adjuvant of livestock vaccines, preparation and applications thereof - Google Patents
Ready-to-use adjuvant of livestock vaccines, preparation and applications thereof Download PDFInfo
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- CN103071153B CN103071153B CN201310021011.3A CN201310021011A CN103071153B CN 103071153 B CN103071153 B CN 103071153B CN 201310021011 A CN201310021011 A CN 201310021011A CN 103071153 B CN103071153 B CN 103071153B
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Abstract
The invention provides a ready-to-use adjuvant of livestock vaccines, preparation and applications thereof, belonging to the field of the adjuvant of livestock vaccines. The ready-to-use adjuvant is prepared from the following substances: 5-30 percent of oil, 0.1-10 percent of hydrophilic surfactant, 0.1-10 percent of oleophilic surfactant, 0.1-10 percent of polymeric micelle substance and 40-90 percent of water. The invention also provides a preparation method of the ready-to-use adjuvant, and the method comprises the following steps: respectively weighing the substances, mixing and then emulsifying, and degerming to obtain the ready-to-use adjuvant of the livestock vaccines. The invention also provides an oil-in-water type vaccine with the ready-to-use adjuvant. The ready-to-use adjuvant is an oil-in-water type adjuvant and has the advantages of simple ingredients, stable dosage form, convenience in use and easiness in injection. The preparation method of the ready-to-use adjuvant has a simple process and is low in cost, and the obtained dosage form is stable. The oil-in-water type vaccine has the advantages of long stable period, easiness in storage, good immune effect, protection period prolonging, easiness in injection and small side reaction.
Description
Technical field
The present invention relates to live vaccine adjuvant field, be specifically related to a kind of compound adjuvant preparation method and the vaccine preparation method containing this compound adjuvant thereof.
Background technology
Oil adjuvant vaccine is known vaccine that can efficient hardening immunity, be one of type that at present domestic and international vaccine market, product is maximum, have three kinds of dosage forms containing oil-adjuvant vaccine: Water-In-Oil (W/O) type, oil-in-water (O/W) type and W/O/W (W/O/W) type.
The application of Water-In-Oil (W/O) type vaccine is the most general, and the remarkable advantage of this dosage form is to obtain the lasting immunoenhancement result of high level; Shortcoming is compared with thickness, inject more difficult, because white oil content in vaccine is relatively high, usually cause serious Side effects, form aseptic suppuration infringement and inoculation position granuloma around simultaneously, can produce outside visible edema, swelling, scleroma and necrosis.Studies have reported that, Water-In-Oil (W/O) dosage form vaccine has the possibility of retention at inoculation position, thereby has hindered the use of vaccine.The animals such as pig, dog, cat are especially responsive to this dosage form vaccine, and this has also limited its application in production reality.
W/O/W (W/O/W) dosage form vaccine has advantages of w/o type and O/W type simultaneously, and effect is fine.Conventional way is first to prepare w/o type vaccine, then through being distributed in water and being prepared from for the second time.Object is to reduce viscosity, is not only convenient to injection but also has good immunogenicity.But difficulty is larger in technology of preparing, vaccine stability is poor.
For reducing the oil content in Emulsion, reduce viscosity, be easy to injection, develop novel adjuvant, and set up oil-in-water (O/W) dosage form vaccine.But the vaccine application of this dosage form is not general, only has commercialization in vaccine for man application aspect, if MF59 adjuvant is for the making of influenza vaccines, not yet applies on animal vaccine.A little less than reason is the immunogenicity of oil-in-water (O/W) dosage form vaccine, only in induced animal body, produce weak immunne response, still can not meet the prevention and control demand of aquaculture epidemic disease.Simultaneously existing oil-in-water (O/W) dosage form vaccine is without the effect of slow control slow release, and primary immune response can not continuous agitation organism immune response, and immune duration is very short.
Summary of the invention
The object of this invention is to provide a kind of instant adjuvant of live vaccine, is oil-in-water type adjuvant, and composition is simple, dosage form is stable, easy to use; The vaccine that this adjuvant and psma ligand are made, good stability, side reaction is little, good immune effect, the protection period is long.
Another object of the present invention is to provide the preparation method of the instant adjuvant of above-mentioned live vaccine.
A further object of the present invention is to provide the oil in water vaccine of the instant adjuvant that contains live vaccine.
Object of the present invention adopts following technical scheme to realize.
An instant adjuvant for live vaccine, is made up of following material according to quality percentage composition:
Oil 5%-30%,
Hydrophilic surfactant active 0.1%-10%,
Lipophilic surfactant 0.1%-10%,
Macromolecule micelle material 0.1%-10%,
Water 40%-90%.
Described oil is the mixture of a kind of in white oil, squalane and Squalene or two kinds.
Described hydrophilic surfactant active is Tween 80, Pu Lunike 121 or its mixture.
Described lipophilic surfactant for department this 80, department this 85 or its mixture.
Described macromolecule micelle material is the mixture of a kind of in chitosan, CARBOPOL 971, hydroxy methocel and GERBU Adjuvant 100 or two kinds.
A preparation method for the instant adjuvant of described live vaccine, the method is specific as follows: take respectively each component, emulsifying after mixing, degerming obtains the instant adjuvant of described live vaccine.
Described emulsification method is colloid mill squeezing and pressing method, microjet method or high pressure homogenization method.
A kind of oil in water vaccine of the instant adjuvant that contains described live vaccine.
Instant adjuvant and inactivation antigen aqueous solution that described oil in water vaccine is 1:0.5-2 by mass ratio form.
Described inactivation antigen aqueous solution is Schweineseuche inactivation of viruses liquid or pig circular ring virus inactivation of viruses liquid.
Beneficial effect:
The instant adjuvant of live vaccine provided by the invention, is oil-in-water type adjuvant, and composition is simple, dosage form is stable, easy to use.Because oily consumption is down to below 30% by 70%, significantly reduce the toxicity to animal, efficiently solve the problem of vaccine side reaction.Macromolecule micelle material is by the mechanism of ionic adsorption and micropore parcel, and the storage that significantly improves antigen is stayed and submission ability, efficiently solves that oil-in-water (O/W) dosage form vaccine immunity activity is weak, short problem of duration.In instant adjuvant, the use amount of oil reduces, and is easy to injection.
The preparation method of instant adjuvant of the present invention, technique is simple, and cost is low, and the dosage form obtaining is stable.
The oil in water vaccine that adopts the instant adjuvant of live vaccine to prepare, stable phase is long, easily stores, good immune effect, the protection period extends, and is easy to injection, and side reaction is very little.
Detailed description of the invention
Further explain the present invention below by embodiment, but the present invention is not subject to the restriction of these embodiment.
Pu Lunike 121(Pluronic L 121) purchased from the Shanghai biological company limited of raw work.
embodiment 1the preparation of adjuvant
Formula 1:
White oil 10 g,
Tween 80 0.5g,
These 85 0.5g of department,
Chitosan 2.0g,
CARBOPOL 971 0.1g,
Water 83.9g.
Formula 2:
Squalane 10 g,
Pu Lunike 121 0.5g,
These 80 0.5g of department,
CARBOPOL 971 3.0g,
Water 83.0g.
Formula 3:
Squalane 10 g, Squalene 10g
Pu Lunike 121 5g, Tween 80 0.3g,
These 80 5g of department, these 85 0.3g of department,
Hydroxy methocel 1.0g, GERBU Adjuvant 100 1.0g,
Water 67.4g.
Formula 4:
Squalane 15g, white oil 15g,
Pu Lunike 121 0.2g, Tween 80 8.8g,
These 80 0.2g of department, these 85 8.8g of department,
Hydroxy methocel 2.0g, CARBOPOL 971 3.0g,
Water 47.0g.
Formula 5:
Squalane 5 g,
Pu Lunike 121 0.1g,
These 80 0.1g of department,
CARBOPOL 971 1.0g, GERBU Adjuvant 100 9.0g,
Water 84.8g.
Formula 6:
Squalane 30 g,
Pu Lunike 121 10g,
These 80 10g of department,
CARBOPOL 971 3.0g,
Water 47.0g.
Adopt and prepare with the following method corresponding instant adjuvant with formula 1-6 respectively: take respectively each component by formula ratio, mix homogeneously after ice-water bath spends the night, with the emulsifying of machinery emulsification method, after 0.22 μ m membrane filtration degerming, obtain respectively instant adjuvant 1-6,4 degree save backup.
Machinery emulsification method is colloid mill squeezing and pressing method, microjet method or high pressure homogenization method.After emulsifying finishes, at the centrifugal 10min of 3000rmp, separate out as qualified without water.
embodiment 2the preparation of oil-in-water type foot and mouth disease vaccine and character thereof
(1) preparation of instant adjuvant
Make instant adjuvant 1-6 by embodiment 1 method.ISA206 adjuvant is purchased from SEPPIC company.
(2) prepare Schweineseuche inactivation of viruses liquid
Schweineseuche inactivation of viruses liquid (O type, II) is provided by Jinyu Baoling Biology Drugs Co., Ltd, and before deactivation, in every 0.2 milliliter of virus liquid, viral level is 10
7.0lD
50/ 0.2 milliliter.This Schweineseuche inactivation of viruses liquid is according to " biological quality quality standard compilation for animals " (2006-2008) related request preparation.Schweineseuche inactivation of viruses liquid (O type, II) is referred to as Schweineseuche inactivation of viruses liquid.
(3) preparation of oil-in-water type foot and mouth disease vaccine
Under aseptic condition, instant adjuvant 1-6 is mixed respectively to the hand even oil-in-water type foot and mouth disease vaccine 1-6 that obtains with Schweineseuche inactivation of viruses liquid.Wherein in oil-in-water type foot and mouth disease vaccine 1, instant adjuvant 1 is 1:0.5 with the mass ratio of Schweineseuche inactivation of viruses liquid.In oil-in-water type foot and mouth disease vaccine 2, instant adjuvant 2 is 1:2 with the mass ratio of Schweineseuche inactivation of viruses liquid.In oil-in-water type foot and mouth disease vaccine 3-6, the mass ratio of instant adjuvant and Schweineseuche inactivation of viruses liquid is 1:1.
Substitute instant adjuvant of the present invention with ISA206 adjuvant and prepare control vaccine A, ISA206 adjuvant and Schweineseuche inactivation of viruses liquid in mass ratio 1:1 mix in emulsion tank, and control vaccine A is prepared in 3000rpm emulsifying for 30 minutes.
(4) comparison of vaccine physical behavior
Detect the physical behavior of oil-in-water type foot and mouth disease vaccine 1-6 and control vaccine A, the stability of more each vaccine.Concrete outcome is in table 1.
The physical behavior comparison of table 1 oil-in-water type foot and mouth disease vaccine 1-6 and control vaccine A
| Vaccine | Outward appearance | Dosage form | Centrifugal stability | 4 DEG C of stability | Viscosity |
| Oil-in-water type foot and mouth disease vaccine 1 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, separate out without water | 19 months stable | 1.0 seconds/0.4ml |
| Oil-in-water type foot and mouth disease vaccine 2 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, separate out without water | 17 months stable | 1.1 seconds/0.4ml |
| Oil-in-water type foot and mouth disease vaccine 3 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, there is 0.1ml to separate out mutually | 18 months stable | 1.6 seconds/0.4ml |
| Oil-in-water type foot and mouth disease vaccine 4 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, there is 0.2ml water to separate out | 17 months stable | 1.5 seconds/0.4ml |
| Oil-in-water type foot and mouth disease vaccine 5 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, separate out without water | 19 months stable | 1.7 seconds/0.4ml |
| Oil-in-water type foot and mouth disease vaccine 6 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, separate out without water | 18 months stable | 1.8 seconds/0.4ml |
| Control vaccine A | Peach even emulsion | W/O/W type | 3000 revs/min, 15 minutes, there is 0.2ml water to separate out | 12 months stable | 2.7 seconds/0.4ml |
Can find out by table 1, the vaccine that adopts instant adjuvant of the present invention to prepare, stability is greater than 17 months, and than contrast Seedling, A is stable.
(5) comparison of vaccine immunity activity and safety
Oil-in-water type foot and mouth disease vaccine 1-6 and control vaccine A are inoculated respectively to 15 mices, inoculate 4 weeks and detect antibody titer by swine foot-and-mouth disease virus ELISA detection kit (Lanzhou Veterinary Inst., Chinese Acedemy of Agaricultural Sciences provides) afterwards, specifically in table 2.As can be seen from Table 2, adopt after vaccine immunity prepared by instant adjuvant of the present invention, the antibody positive rate of mice is all higher than 80%, at least higher by 10% than matched group, illustrates that instant adjuvant of the present invention can significantly strengthen immune effect.Diet and the mental status of after immunity, observing mice every day, observe injection site skin and have or not the abnormal response such as ulceration, projection, and randomly draw 5 mices in every group of latter 14 days of immunity, dissects, and observes the variation of injection portion tissue.Result (table 2) is visible, and each group of pig of immune oil-in-water type foot and mouth disease vaccine is all normal, without any side reaction, illustrates that instant adjuvant of the present invention is because oily use amount is few, and side reaction is very little, and is easy to injection.
Immunocompetence and the safety comparison of table 2 vaccine 1 and control vaccine A
| Vaccine | TPPA | Side reaction |
| Oil-in-water type foot and mouth disease vaccine 1 | 4 weeks antibody positive rate 80% after mouse immune | After 10 mouse immunes, injection site does not all have lump to occur |
| Oil-in-water type foot and mouth disease vaccine 2 | 4 weeks antibody positive rate 80% after mouse immune | After 10 mouse immunes, injection site does not all have lump to occur |
| Oil-in-water type foot and mouth disease vaccine 3 | 4 weeks antibody positive rate 90% after mouse immune | After 10 mouse immunes, injection site does not all have lump to occur |
| Oil-in-water type foot and mouth disease vaccine 4 | 4 weeks antibody positive rate 80% after mouse immune | After 10 mouse immunes, injection site does not all have lump to occur |
| Oil-in-water type foot and mouth disease vaccine 5 | 4 weeks antibody positive rate 90% after mouse immune | After 10 mouse immunes, injection site does not all have lump to occur |
| Oil-in-water type foot and mouth disease vaccine 6 | 4 weeks antibody positive rate 90% after mouse immune | After 10 mouse immunes, injection site does not all have lump to occur |
| Control vaccine A | 4 weeks antibody positive rate 70% after mouse immune | After 10 mouse immunes, there are 2 injection sites to have lump, within 1 week, disappear |
embodiment 3the application of oil-in-water type pig circular ring virus vaccine
(1) prepare porcine circovirus 2 type inactivation of viruses liquid
Porcine circovirus 2 type inactivation of viruses liquid (DBN-SX07 strain) is provided by Tian Bang bio tech ltd, Chengdu, and before deactivation, every milliliter of virus liquid viral level is 10
5.5tCID
50.This inactivation of viruses liquid meets " biological quality quality standard compilation for animals " (2006-2008) related request.
(2) preparation of oil-in-water type pig circular ring virus vaccine
Mix respectively hand even preparation oil-in-water type pig circular ring virus vaccine 1-6 with porcine circovirus 2 type inactivation of viruses liquid with instant adjuvant 1-6.Wherein in oil-in-water type pig circular ring virus vaccine 1, instant adjuvant 1 is 1:0.5 with the mass ratio of porcine circovirus 2 type inactivation of viruses liquid.In oil-in-water type pig circular ring virus vaccine 2, instant adjuvant 2 is 1:2 with the mass ratio of porcine circovirus 2 type inactivation of viruses liquid.In oil-in-water type pig circular ring virus vaccine 3-6, the mass ratio of instant adjuvant and porcine circovirus 2 type inactivation of viruses liquid is 1:1.
Substitute instant adjuvant of the present invention with ISA206 adjuvant and prepare control vaccine B, ISA206 adjuvant and porcine circovirus 2 type inactivation of viruses liquid in mass ratio 1:1 mix in emulsion tank, and 3000rpm emulsifying obtain control vaccine B for 30 minutes.
(3) comparison of vaccine physical behavior
Detect the physical behavior of oil-in-water type pig circular ring virus vaccine 1-6 and control vaccine A, the stability of more each vaccine.Concrete outcome is in table 3.
The physical behavior comparison of table 3 oil-in-water type pig circular ring virus vaccine and control vaccine B
| Vaccine | Outward appearance | Dosage form | Centrifugal stability | 4 DEG C of stability | Viscosity |
| Oil-in-water type pig circular ring virus vaccine 1 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, separate out without water | 19 months stable | 1.2 seconds/0.4ml |
| Oil-in-water type pig circular ring virus vaccine 2 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, separate out without water | 20 months stable | 1.2 seconds/0.4ml |
| Oil-in-water type pig circular ring virus vaccine 3 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, there is 0.2ml to separate out mutually | 17 months stable | 1.6 seconds/0.4ml |
| Oil-in-water type pig circular ring virus vaccine 4 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, there is 0.2ml water to separate out | 17 months stable | 1.6 seconds/0.4ml |
| Oil-in-water type pig circular ring virus vaccine 5 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, separate out without water | 19 months stable | 1.9 seconds/0.4ml |
| Oil-in-water type pig circular ring virus vaccine 6 | Milky even emulsion | O/W type | 3000 revs/min, 15 minutes, separate out without water | 20 months stable | 2.1 seconds/0.4ml |
| Control vaccine B | Peach even emulsion | W/O/W type | 3000 revs/min, 15 minutes, there is 0.2ml water to separate out | 12 months stable | 2.7 seconds/0.4ml |
Can find out by table 3, the vaccine that adopts instant adjuvant of the present invention to prepare, stability is greater than 17 months, is significantly better than control vaccine B.
(4) immunocompetence comparison
70 of the 14 age in days piglets of getting health, pig circular ring virus antibody and antigen negative, are divided into 7 groups, 10 every group.By oil-in-water type pig circular ring virus vaccine 1-6 and control vaccine B immune one group of piglet respectively, immune step is: exempt from 14 age in days head, 35 ages in days carry out two exempts from, and immunizing dose is 1.0ml vaccine/head.In last immunity latter 1 month, 2 months, 3 months, 4 months and 5 months, blood sampling.Respectively by serum sample by 800 times of dilutions, carry out antibody test with pig circular ring virus antibody ELISA test kit (Wuhan Ke Qian biological product company limited), add up antibody positive rate.
The immunocompetence comparison of table 4 oil-in-water type pig circular ring virus vaccine and control vaccine B
Note: same column does not represent significant difference, P<0.05 containing same letter.
Can find out by table 4, the immune effect of vaccine that adopts instant adjuvant of the present invention to prepare is good, immune duration can reach 5 months, and the immune duration of control vaccine B only has 3 months (according to the requirement of " veterinary biologics quality standard compilation " (2010), antibody positive rate >=80% is qualified).The vaccine that adopts instant adjuvant of the present invention to prepare meets the immune diseases prevention requirement of market pig completely, is significantly better than control vaccine B, has extraordinary using value.
(5) side reaction comparison
In the present embodiment title (4), the piglet after 14 age in days head exempt from carries out the immunity temperature check of latter 7 days, and concrete outcome is in table 5.As can be seen from Table 5, after oil-in-water type pig circular ring virus vaccine 1-6 immunity, pig body temperature is all within the normal range of 39.0-40.0 DEG C, and without heating paresthesia, and control vaccine B head exempts from rear 2-5 days, and pig body temperature is greater than 40.0 degree.Meanwhile, the pig after head is exempted from characterizes inspection, and the pig of immune oil-in-water type pig circular ring virus vaccine 1-6 is not found the abnormal phenomenas such as injection site damage, ulcer; And the pig of immune control vaccine B has 2 injection sites to have lump, within 1 week, disappear.The above results explanation, the vaccine that adopts instant adjuvant of the present invention to prepare, after immune swine side reaction very little, to pig safety.
Mean body temperature after every group of pig immunity of table 5 change (DEG C)
| Group | 0d | 1d | 2d | 3d | 4d | 5d | 6d | 7d |
| Oil-in-water type pig circular ring virus vaccine 1 | 39.2 | 39.8 | 39.9 | 39.8 | 39.5 | 39.4 | 39.3 | 39.2 |
| Oil-in-water type pig circular ring virus vaccine 2 | 39.1 | 3.97 | 40.0 | 39.5 | 39.7 | 39.5 | 39.5 | 39.4 |
| Oil-in-water type pig circular ring virus vaccine 3 | 39.3 | 39.5 | 39.6 | 39.6 | 39.3 | 39.4 | 39.5 | 39.3 |
| Oil-in-water type pig circular ring virus vaccine 4 | 39.3 | 39.6 | 39.9 | 39.5 | 39.7 | 39.6 | 39.5 | 39.4 |
| Oil-in-water type pig circular ring virus vaccine 5 | 39.2 | 39.8 | 39.9 | 39.6 | 39.4 | 39.4 | 39.4 | 39.5 |
| Oil-in-water type pig circular ring virus vaccine 6 | 39.2 | 40.0 | 40.0 | 39.9 | 39.4 | 39.3 | 39.5 | 39.3 |
| Control vaccine B | 39.2 | 40.0 | 40.3 | 40.3 | 40.2 | 40.3 | 40.0 | 39.5 |
Claims (6)
1. an instant adjuvant for live vaccine, is made up of following material according to quality percentage composition:
Oil 5%-30%,
Hydrophilic surfactant active 0.1%-10%,
Lipophilic surfactant 0.1%-10%,
Macromolecule micelle material 0.1%-10%,
Water 40%-90%;
Described oil is the mixture of a kind of in white oil, squalane and Squalene or two kinds; Described hydrophilic surfactant active is Tween 80, Pu Lunike 121 or its mixture; Described lipophilic surfactant for department this 80, department this 85 or its mixture; Described macromolecule micelle material is the mixture of a kind of in chitosan, CARBOPOL 971, hydroxy methocel and GERBU Adjuvant 100 or two kinds; Described live vaccine is foot and mouth disease vaccine or pig circular ring virus vaccine, and described instant adjuvant is oil-in-water type.
2. a preparation method for the instant adjuvant of live vaccine described in claim 1, is characterized in that the method is specific as follows: take respectively each component, and emulsifying after mixing, degerming obtains the instant adjuvant of described live vaccine.
3. the preparation method of the instant adjuvant of live vaccine according to claim 2, is characterized in that described emulsification method is colloid mill squeezing and pressing method, microjet method or high pressure homogenization method.
4. an oil in water vaccine that contains the instant adjuvant of live vaccine described in claim 1.
5. oil in water vaccine according to claim 4, is characterized in that: instant adjuvant and inactivation antigen aqueous solution that described oil in water vaccine is 1:0.5-2 by mass ratio form.
6. oil in water vaccine according to claim 5, is characterized in that described inactivation antigen aqueous solution is Schweineseuche inactivation of viruses liquid or pig circular ring virus inactivation of viruses liquid.
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| CN103610641B (en) * | 2013-11-29 | 2016-05-04 | 吴福文 | Two-phase oil emulsion adjuvant and preparation method thereof for live vaccine |
| CN106267183B (en) * | 2015-06-09 | 2023-02-28 | 普莱柯生物工程股份有限公司 | Live vaccine composition containing adjuvant and preparation method and application thereof |
| CN106344920B (en) * | 2015-07-16 | 2020-11-27 | 普莱柯生物工程股份有限公司 | Adjuvant for vaccine and application thereof |
| CN105879025A (en) * | 2015-11-19 | 2016-08-24 | 李锁霞 | Immunologic adjuvant composition and preparation method thereof |
| CN107050449A (en) * | 2016-10-19 | 2017-08-18 | 天津佐沐生物科技有限公司 | A kind of oil in water vaccine adjuvant and preparation method thereof |
| CN106511996B (en) * | 2016-11-04 | 2019-09-10 | 江苏省农业科学院 | Emulsion type adjuvant and preparation method thereof for aftosa vaccine |
| CN109806391A (en) * | 2017-11-22 | 2019-05-28 | 西北民族大学 | The preparation method and applications of Water Soluble Compound adjuvant are immunized in a kind of live vaccine |
| CN108079288B (en) * | 2018-02-09 | 2022-04-26 | 天康生物制药有限公司 | Vaccine, emulsification process of vaccine and application |
| CN108324941A (en) * | 2018-04-03 | 2018-07-27 | 林淑卿 | Pig disease vaccine adjuvant and preparation method thereof |
| CN111494619B (en) * | 2020-04-26 | 2022-03-18 | 南京农业大学 | Preparation method of squalene-based cationic nanostructured lipid carrier immunologic adjuvant |
| CN113797328A (en) * | 2020-06-16 | 2021-12-17 | 浙江洪晟生物科技股份有限公司 | Compound adjuvant for animal vaccine, preparation method and vaccine |
| CN111840214B (en) * | 2020-08-21 | 2022-03-15 | 江苏省农业科学院 | Temperature-sensitive hydrogel adjuvant of veterinary vaccine, preparation method and application thereof |
| CN112641939B (en) * | 2020-12-28 | 2024-04-02 | 吉林冠界生物技术有限公司 | Water-in-oil type composite adjuvant, preparation method and application thereof, and preparation method of vaccine |
| CN117442716B (en) * | 2023-12-26 | 2024-03-15 | 金宇保灵生物药品有限公司 | Vaccine adjuvant for animals and preparation method and application thereof |
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| CN101108249A (en) * | 2006-07-18 | 2008-01-23 | 洛阳普莱柯生物工程有限公司 | Triple killed vaccine for fowl and method of preparing the same |
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